Cytokine Changes in Cerebrospinal Fluid Following Vascular Surgery on the Thoracic Aorta

Cytokine Changes in Cerebrospinal Fluid Following Vascular Surgery on the Thoracic Aorta | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Article Cytokine Changes in Cerebrospinal Fluid Following Vascular Surgery on the Thoracic Aorta Christopher Pereira, Anisha H. Perera, Nung Rudarakanchana, Benjamin H. L Harris, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1602134/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract Background: There is growing evidence that surgery can drive an inflammatory response in the brain. However, the mechanisms behind this response are incompletely understood. Neuroinflammation may contribute to peri-operative neurocognitive disorders (PND), including post-operative delirium (POD). Here, we investigate the hypotheses that 1. Cerebrospinal fluid (CSF) cytokines increase after vascular surgery and 2. That these changes in CSF cytokines are interrelated. Methods: Patients undergoing either open or endovascular elective surgery of the thoracic aorta were invited to participate in this study. Cerebrospinal fluid samples were taken before surgery and on the first post-operative day. These were analysed for the presence of ten cytokines by immunoassay to examine for post-operative changes in cytokine levels. Results: After surgery, there were significant increases in six out of the ten measured CSF cytokines (IL-1β, 2, 6, 8, 10 and 13). This included changes in both putative pro-inflammatory (IL-1β, 6 and 8) and putative anti-inflammatory (IL-2, 10 and 13) cytokines. The greatest increases occurred in IL-6 and IL-8, which showed a 63-fold and a 31-fold increase respectively. There was strong intercorrelation between CSF cytokines after the operation. Conclusions: Following surgery on the thoracic aorta, there was a marked increase in CSF cytokines, consistent with a potential role in neuroinflammation. The ten measured cytokines showed intercorrelation after the operation, indicating that a balance between multiple pro- and anti-inflammatory cytokines may be present. This could be detrimental, protective, or both. Neuroinflammation cerebrospinal fluid vascular surgery cytokines interleukins central nervous system Figures Figure 1 Figure 2 Background: Neuroinflammation and its role in delirium and post-operative cognitive dysfunction is complex and incompletely understood. For example, neuroinflammation can lead to Alzheimer’s disease (AD) progression [1, 2]. On the other hand, a degree of neuroinflammation in AD may be protective, as the cytokines IL-6 and TNF-α are involved in the clearance of amyloid plaques [3, 4]. This raises the question of whether the neuroinflammatory process could also drive peri-operative neurocognitive disorders (PND), such as post-operative delirium (POD). PND is the commonest post-operative complication in older patients undergoing surgery and is associated with worse clinical outcomes [5]; understanding its pathophysiology is essential for developing prevention and cure. One hypothesis for the aetiology of PND is that a physiological insult from surgery induces the release of local inflammatory mediators (such as cytokines) from macrophages at the surgical site [6]. An intact blood-brain-barrier (BBB) prevents these inflammatory mediators from affecting the closely regulated environment of the CNS. However if the BBB is weakened by aging, neurodegeneration [7], or the response to a surgical insult [8], inflammatory mediators can enter the CNS. The processes by which the BBB may become weakened are complex, but in AD, this includes brain capillary leakage, cellular infiltration, degeneration of pericytes and loss of endothelial integrity [7]. Once inflammatory mediators enter the CNS, microglial activation occurs, which drives further inflammation, partly through cytokine release [9, 10]. Cytokine release and the inflammatory response can then trigger neuronal injury and dysfunction [7], which theoretically could manifest as PND. There is currently no treatment for PND [11]. If the process of neuroinflammation can be better understood, this may open the door to cytokine manipulation, potentially reducing levels of consequent PND. Previous investigations on peri-operative cytokine changes has shown greater increases in CSF cytokines than serum or plasma cytokines after an operation [12, 13, 14]. This suggests a key role for CSF cytokines in post-operative neuroinflammation. However, the number of patients involved in these studies was small. There is a further suggestion that the CSF cytokines, IL-6 and IL-8, are increased in patients with worse neurocognitive outcomes, but again the sample sizes of these studies are inadequately powered to provide definitive evidence [13, 15]. To date, only one study has investigated peri-operative changes in both CSF and serum following vascular surgery on the thoracic aorta [16]. In this study of 23 patients, the cytokine IL-6 was increased in both serum and CSF after the operation. In patients with spinal cord injury, the CSF IL-6 increase was more marked. While this study examined a wide variety of proteins relevant to neurology, the number of cytokines studied was small. Spinal cord injury leading to paraplegia is the most devastating consequence of morbidity following surgery on the thoracic aorta [17]. Draining CSF intraoperatively with a spinal catheter has been shown to reduce the chances of this complication [18], by increasing blood flow to the spinal cord [19]. As such patients already have a spinal catheter in place. This allows for easy access to CSF peri-operatively, making patients undergoing thoracic-vascular surgery a valuable cohort for studying neuroinflammation. We investigated cytokines with both a pro-inflammatory role (IL-1β, IL-6, IL-8, IL-12p70, IFN-γ and TNF-α) and those with an anti-inflammatory role (IL-2, IL-4, IL-10 and IL-13) [20, 21] in a cohort of patients undergoing vascular surgery. The aim of this study was to evaluate the neuroinflammatory response to vascular surgery in order to: Determine changes in pro- and anti-inflammatory CSF cytokines before and after vascular surgery. Investigate potential intercorrelations between cytokines in the CSF, to establish whether multiple cytokines are involved in driving neuroinflammation. Establish if the changes in CSF cytokines are reflected in serum cytokine levels. If so, this would enable serum cytokines to be used as biomarkers of CSF changes. Methods: This was a prospective observational study looking at peri-operative changes in cytokine levels in the CSF and serum of patients undergoing elective vascular surgery for any pathology of the thoracic aorta. Study population Patients were eligible for recruitment into the study if they were undergoing either open or endovascular repair for any thoracic aortic pathology in which a spinal catheter was to be used as part of standard peri-operative care. The decision about whether a spinal catheter would be used during an operation was a joint decision made pre-operatively in the vascular multidisciplinary team meeting involving the operating surgeon and anaesthetist. Patients did not have neuroimaging performed before or after the operation. Recruitment took place at St Mary’s Hospital, London, over a one-year period. Patients unable to give informed written consent were excluded from the study. The study received approval from the London Westminster Research Ethic Committee (13/LO/0210). The study conformed to the precepts set out in the Declaration of Helsinki of 1975. All patients gave informed, written consent prior to surgery. Specimen collection and storage Study patients had a spinal catheter inserted prior to surgery by an anaesthetist, following administration of a general anaesthetic. The spinal catheter was used to maintain the CSF pressure at 10mmHg. If the pressure rose above 10mmHg, CSF was slowly drained until the target was met. CSF was collected by the same operator (author AP) prior to surgery and on the first post-operative day. Approximately 1-3mL of CSF was collected each time. The spinal catheter was removed when it was no longer clinically indicated. Samples were centrifuged at 4000RPM for 5 min to remove any red blood cells present in the sample. Samples were then pipetted into cryo-tubes in 500μL aliquots and stored in a -80ºC freezer. Immunoassays The V-PLEX Proinflammatory Panel 1 Human Kit (Meso Scale Discovery, Maryland, USA) was chosen as it measures both pro-inflammatory (IL-1β, IL-6, IL-8, IL-12p70, IFN-γ and TNF-α) and anti-inflammatory (IL-2, IL-4, IL-10 and IL-13) cytokines [21]. Analysis followed the manufacturer’s instructions (www.mesoscale.com). This method of cytokine measurement in peri-operative CSF and blood samples has been used previously [12]. It uses electrochemiluminescence to quantify the levels of ten cytokines in 25 μL of peri-operative CSF or blood samples. The range for the lowest level of detection (LLD) was between 0.00861 pg/mL for IL-4 and 0.605 pg/mL for IFN-γ. If samples were above the upper limit of detection (ULD) for the assay, they were diluted in Diluent 2 which was supplied with the kit assay and re-analysed, according to the manufacturer’s instructions. This was necessary for a small number of IL-8 measurements. For cytokine levels below the LLD or detected, but below the fit curve, the LLD value for the cytokine assay was used, as previously described [22]. All cytokine analysis was completed in the Infectious Diseases Laboratory at Imperial College London, London. Statistical Analysis Analyses were carried out using Python, version 3.7 (available from www.python.org). A Wilcoxon Signed-Rank test with Bonferroni correction was used to examine changes in cytokines before and after surgery. Spearman’s rank correlation coefficient, again with a Bonferroni correction, assessed cytokine intercorrelation. An adjusted-p value of <0.05 was considered statistically significant. A power calculation to determine the necessary sample size was not undertaken before starting the study, as the number of patients who would be able to consent and complete the study was anticipated to be small. Results: During a 1-year period, ten patients were recruited into the study. Table 1 shows the demographic and pre-operative information for the patients. Four of the patients were female, with a mean age of 65 yrs (SD 12 years). Seven patients had undergone previous vascular surgery, often with serious post-operative morbidity. Two patients died in critical care within 30-days of the operation. No patient developed post-operative paraplegia or a clinically apparent stroke. Timetable of sample collection All patients had pre-operative (timepoint 1: T1) and post-operative (timepoint 2: T2) CSF samples taken. Five patients also had simultaneous paired serum samples. Patient 5 had their post-operative samples taken on the day of surgery. Supplementary table S1 summarises the aetiology of the thoracic aorta pathology, the type of vascular surgery and the post-operative complications. Cytokine changes following surgery Table 2 and Figure 1 show the cytokine changes in CSF following surgery. The greatest increases occurred in IL-6 and IL-8, which showed a 63-fold and a 31-fold increase respectively. Six cytokines showed statistically significant increases between T1 and T2 (IL-1β, 2, 6, 8, 10 and 13), as shown in Figure 1. Of the cytokines which showed statistically significant increases, three are traditionally classified as pro-inflammatory (IL-1β, 6 and 8) and three (IL-2, 10 and 13) as anti-inflammatory [20]. The levels of most CSF cytokines tended to rise following surgery. However, levels of IFN-γ and IL-12p70 were generally below the LLD in both the pre-and post-operative CSF samples, so no change could be detected. For the cytokines IL-1β, IL-2 and IL-4, pre-operative levels were often below the LLD, but post-operative levels rose into the detection range. Intercorrelation between CSF cytokines Figure 2 shows the intercorrelation between CSF cytokines before and after surgery. At T1, the significant correlations observed in the CSF were between IL-1β and IL-2 (r = 0.95, adjusted- p <0.001). At T2, there were a number of strong positive correlations between 20 pairs of different cytokines, as shown in Supplementary table S2. Serum cytokine changes Only five of the ten patients had serum samples drawn at the same time as the CSF samples. The greatest increase was in IL-6 which showed a 71-fold increase in serum levels after the operation. There was limited intercorrelation between CSF and serum cytokines. At T1, four combinations of CSF and serum cytokines showed significant correlation (r = 1, adjusted- p <0.05). These included IL-2 and IL-1β, IL-4 and IL-12, IFN-γ and Il-2 and IL-1β and IL-1β. At T2 there were no significant correlations between the CSF and serum cytokine levels (data not shown). Discussion: CSF cytokine findings We demonstrated increases in both pro- and anti-inflammatory CSF cytokines after vascular surgery on the thoracic aorta. The most marked increases occurred in the pro-inflammatory cytokines, IL-6 and IL-8. The increases in CSF IL-6 confirm previous findings in a similar cohort [16], whereas, to our knowledge, we are the first group to show similar changes in CSF IL-8. Interleukin-8 is a member of the CXC chemokine family, implicated in a wide variety of inflammatory diseases [23]. CSF IL-8 has been shown to be increased in AD, Parkinson’s disease [24] and following traumatic brain injury [25]. In patients undergoing other forms of surgery, findings of marked increases in CSF IL-8 have also been demonstrated [12, 14]. The increase in CSF cytokines in this study could have resulted from a dysregulated inflammatory response to the peripheral stimulus of surgery driving neuroinflammation within the brain. Alternatively, these findings may have been secondary to silent cerebral infarcts, which have been shown to be increased following thoracic aortic endovascular procedures [26]. Ischaemic strokes have been shown to drive an increase in proinflammatory cytokines [27]. It is also possible that the CSF cytokine changes may have occurred due to other post-operative complications such as endoleaks or infection. Intercorrelation findings Levels of cytokines in the CSF, while not exhibiting an association with each other prior to surgery, strongly correlate on day one after surgery. Figure 2 highlights the complex balance between pro- and anti-inflammatory cytokines which may drive neuroinflammation. The lack of an association between post-operative CSF and serum samples is consistent with other studies in this area [12, 14], and suggests that changes in cytokine levels in blood cannot be used reliably as surrogate markers of CSF cytokine changes. Proposed mechanisms The results of this study need to be interpreted alongside the current postulated mechanisms of brain dysfunction. These include excessive neuroinflammation [28], the production of reactive oxygen species (ROS) [29], and dysregulated neurotransmission [30]. These mechanisms are all mediated through activation of microglia, which when stimulated can release ROS [29] and cytokines [31]. Microglia are also key drivers of the kynurenine inflammatory pathway, which, in turn, can drive glutamatergic neurotransmission [32]. In the healthy brain, microglia are fundamental in maintaining tissue homeostasis by removing accumulated debris [29]. However, their overactivity may be harmful in disease states [33]. The postulated mechanisms of brain dysfunction are not mutually exclusive, with multiple mechanisms likely to be acting together [30]. Indeed, pro-inflammatory cytokines have been shown to activate the kynurenine pathway, which in turn leads to the generation of ROS through quinolinic acid production [34]. The cytokine changes demonstrated in this study may therefore have implications for several mechanisms of brain dysfunction. Therapeutic targets In contrast to neurodegenerative processes, peri-operative brain dysfunction occurs at a predictable time point, giving a potential opportunity for prevention [35]. Currently, no effective treatment for PND exists [36]. The suggestion that CSF IL-6 and IL-8 hold a key role in the post-operative neuroinflammatory pathway, raises the question of whether direct cytokine inhibition could attenuate these effects. However, as we have demonstrated in this paper, multiple cytokines, both pro- and anti-inflammatory, increase after an operation and thus blocking the action of only one of these cytokines may not necessarily inhibit neuroinflammation. Furthermore, as has been suggested in Alzheimer’s disease, a degree of cytokine-driven neuroinflammation may be neuroprotective [3,4]. Limitations Similar to many studies in this area, this study had a small patient cohort, which may have limited our ability to demonstrate the true magnitude of peri-operative cytokine changes. Future studies should involve larger sample sizes across multiple settings to address this problem. Samples were only taken at two time points, with one patient’s CSF sample taken after surgery on day 0 rather than day 1. This patient was not excluded due to an already small cohort. Within the cohort, the surgical approach was not homogenous, with some patients undergoing open surgery and others undergoing endovascular surgery, which could represent a further complicating factor. The small numbers of patients in different surgical groups limits meaningful comparisons. A further confounder was that seven out of ten patients had undergone previous vascular surgery, often with serious post-operative morbidity. Ideally, this study would have corrected for underlying co-morbidity and baseline inflammatory status. In future studies, neuroimaging, to look for radiological evidence of stroke, should be included to investigate how much of the neuroinflammatory burden may be driven by ischaemic strokes. Finally, we cannot exclude the possibility that the inflammatory response was driven by the insertion of the spinal catheter, rather than surgery or anaesthesia, but this is felt to be unlikely due to the magnitude of cytokine changes [14]. This study looked solely at cytokine changes, which is only part of the neuroinflammatory process after surgery [35]. Measurement of the Q-albumin to determine the integrity of the BBB would also have been useful [7]. Future studies would ideally also examine the CSF cell count and immunoglobulin subtypes [37], and other markers of neuronal injury [8] to more fully understand pathophysiological processes. This was not possible within the scope of this study. A final key limitation of this study was that patients did not undergo peri-operative cognitive testing. Formal cognitive testing for delirium, using screening tools such as the 4AT [38] and neuropsychological testing, would allow for the more direct investigation of correlations between observed CSF cytokine changes and the magnitude of cognitive dysfunction in PND. Conclusions: After vascular surgery there is a large increase in cytokines in the CSF, particularly in the pro-inflammatory cytokines IL-6 and IL-8. This may be secondary to peripheral changes in the circulation crossing the BBB and driving neuroinflammation. A strong correlation was found between CSF cytokines on day one after the operation, suggesting that it may be the balance between multiple pro- and anti-inflammatory cytokines which drives neuroinflammation. Abbreviations: AD, Alzheimer’s disease; BBB, Blood-brain barrier; CNS, Central nervous system; CSF, Cerebrospinal fluid; IFN-γ, Interferon gamma; IL, Interleukin; LLD, Lower limit of detection; POD, Post-operative delirium; PND, Peri-operative neurocognitive disorders; ROS, Reactive oxygen species; T1, Time-point 1 (pre-operation); T2, Time-point 2 (day 1 post-operation); TEVAR, Thoracic endovascular aortic repair; TNF-α, Tumour necrosis factor alpha; ULD, Upper limit of detection. Declarations: Ethics approval and consent to participate The study received approval from the London Westminster Research Ethic Committee (13/LO/0210). The study conformed to the precepts set out in the Declaration of Helsinki of 1975. All patients gave informed, written consent prior to surgery. Availability of data and materials The dataset supporting the conclusions of this article is available from the corresponding author upon reasonable request. Competing interests The authors declare no competing interests. Funding The study was funded by a grant awarded to Miss Rudarakanchana from the National Institute of Health Research (NIHR) Imperial Biomedical Research Centre (BRC) Acknowledgements The authors acknowledge the United Kingdom National Institute for Health Research (NIHR) Biomedical Facility at Imperial College London for infrastructure support. SDT-R was funded by a Wellcome Trust ISSF grant at Imperial College London Author contributions C.P. – undertook all cytokine experiments and writing of the manuscript. A.H.P. was responsible for patient recruitment and biofluid collection. N.R. offered supervision with the project M.D. – undertook manuscript review. B.H.L.H. – undertook statistical analysis. M.D.G. – undertook statistical analysis. S.D.T.R. – offered guidance and supervision with the project and manuscript review. M.F. – was responsible for supervision of the project and manuscript review. 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Tables Table 1: Demographic and Pre-operative Information ID Sex Age Past Medical History Past Surgical History Drug History 4 F 73 HTN, high cholesterol, ex-smoker Carotid-subclavian bypass Bisoprolol, paracetamol, simvastatin 5 M 80 CABG, high cholesterol, prostate cancer Radical prostatectomy, EVAR Aspirin, simvastatin, omeprazole, paracetamol 10 F 56 Endometriosis, HTN, high cholesterol, ex-smoker Hybrid-vascular surgery (2008) Atorvastatin, amlodipine, perindopril 12 F 77 Left occipital ischaemic stroke, asthma, IHD, T2DM, high cholesterol, HTN Nil NR 13 F 40 HTN, Marfan syndrome with pectus excavatum and dural ectasia, heart failure Type A aortic dissection - emergency aortic valve sparing open replacement of root/ascending aorta and proximal arch (2007), arch hybrid (2012)- post operative cardiac arrest followed by tracheostomy, myopathy and prolonged ITU stay. Amlodipine, perindopril, bisoprolol, aspirin, spironolactone 18 M 54 Marfan syndrome, ICD, blind, bilateral cataracts, stroke, HTN, high cholesterol, T2DM Open arch and DTA replacement, AVR, and ascending aorta to LCCA bypass, post operative occipital infarct, haemorrhage and large SDH requiring craniotomy and evacuation. Amlodipine, indapamide, metoprolol, senna, doxazosin, gliclazide, losartan, pregabalin, lansoprazole, paracetamol, warfarin, tinzaparin, 20 M 74 Paraplegia, CKD Open type 2 thoracic aorta repair (2000), then dilatation of visceral aortic patch NR 24 M 62 HTN Nil Carvedilol 25 M 72 HTN, high cholesterol, current smoker, T2DM, COPD Nil NR 27 M 65 HTN, high cholesterol, smoker, COPD, schizophrenia EVAR (2013) Amlodipine, procyclidine Key: AVR = Aortic valve replacement, CKD = Chronic kidney disease, CABG = Coronary artery bypass graft, COPD = Chronic obstructive pulmonary disease, DTA = Descending thoracic aorta, EVAR = Endovascular aneurysm repair, HTN = Hypertension, ICD = Implantable Cardioverter Defibrillator, IHD = Ischaemic heart disease, ITU = Intensive therapy unit, LCCA = left common carotid artery, NR = Not recorded, SHD = Subdural haematoma, T2DM = Type 2 Diabetes Legend: A table showing the medical and surgical backgrounds for the ten patients included in this study. Table 2: Summary of cytokine measurements in CSF Cytokine Timepoint CSF Median [IQR] (pg/mL) Adjusted- p value Wilcoxon Signed-Rank Test between T1 and T2 Average fold change IL-1β T1 T2 0.14 [0.14 – 0.15] 0.60 [0.36 – 0.84] <0.01 5.4 IL-2 T1 T2 0.20 [0.20 – 0.23] 0.30 [0.21 – 0.81] <0.05 4.6 IL-4 T1 T2 0.02 [0.01 – 0.03] 0.03 [0.01 – 0.08] ns 4.5 IL-6 T1 T2 0.98 [0.39 – 1.28] 15.91 [9.73 – 62.57] <0.01 63.3 IL-8 T1 T2 26.85 [9.35 – 42.32] 919.23 [333.42 – 1366.63] <0.01 31.0 IL-10 T1 T2 0.30 [0.19 – 0.43] 0.85 [0.37 – 1.00] <0.05 4.5 IL-12p70 T1 T2 0.09 [0.08 – 0.17] 0.11 [0.08 – 0.12] ns 2.8 IL-13 T1 T2 1.14 [0.55 – 1.86] 2.78 [1.67 – 12.75] <0.01 5.2 IFN-γ T1 T2 0.605 [0.54 – 0.67] 0.605 [0.54 – 0.63] ns 2.6 TNF-α T1 T2 0.52 [0.32 – 0.96] 0.99 [0.51 – 2.10] ns 3.9 Legend: Cytokine levels in cerebrospinal fluid (CSF) before surgery (T1) and the day after surgery (T2), ns = non-significant Additional Declarations No competing interests reported. Supplementary Files Supplementaryinformation22.4.pdf Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major revision 28 Jun, 2022 Reviews received at journal 25 Jun, 2022 Reviewers agreed at journal 13 Jun, 2022 Reviewers invited by journal 11 May, 2022 Editor assigned by journal 11 May, 2022 Editor invited by journal 29 Apr, 2022 Submission checks completed at journal 29 Apr, 2022 First submitted to journal 27 Apr, 2022 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1602134","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":102451451,"identity":"05071177-63e0-4e3f-b82d-efa0c6cadcc6","order_by":0,"name":"Christopher Pereira","email":"","orcid":"","institution":"Cutrale Perioperative and Ageing Group, Department of Bioengineering, Imperial College London, London","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Christopher","middleName":"","lastName":"Pereira","suffix":""},{"id":102451452,"identity":"1284208c-0dfd-4b52-92c2-f07c13e9b108","order_by":1,"name":"Anisha H. Perera","email":"","orcid":"","institution":"Imperial Vascular Unit, Department of Surgery and Cancer, Imperial College London, London","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Anisha","middleName":"H.","lastName":"Perera","suffix":""},{"id":102451453,"identity":"b2183d38-8131-45e4-9bc7-e50dc5848070","order_by":2,"name":"Nung Rudarakanchana","email":"","orcid":"","institution":"Imperial Vascular Unit, Department of Surgery and Cancer, Imperial College London, London","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nung","middleName":"","lastName":"Rudarakanchana","suffix":""},{"id":102451454,"identity":"92a83360-7d0e-4411-a3d7-31f093f1de42","order_by":3,"name":"Benjamin H. L Harris","email":"","orcid":"","institution":"Computational Biology and Integrative Genomics, Department of Oncology, University of Oxford, Oxford","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Benjamin","middleName":"H. L","lastName":"Harris","suffix":""},{"id":102451455,"identity":"4775adbb-4072-4ad6-8ee0-924d79745958","order_by":4,"name":"Matteo Giovannantonio","email":"","orcid":"","institution":"Computational Biology and Integrative Genomics, Department of Oncology, University of Oxford, Oxford","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Matteo","middleName":"","lastName":"Giovannantonio","suffix":""},{"id":102451456,"identity":"b12953ff-84b4-4694-a556-1de5ed43f461","order_by":5,"name":"Simon D. Taylor-Robinson","email":"","orcid":"","institution":"Department of Surgery and Cancer, Imperial College London, London","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Simon","middleName":"D.","lastName":"Taylor-Robinson","suffix":""},{"id":102451457,"identity":"03a58d8d-6a2e-4092-a3fb-46e909a341ae","order_by":6,"name":"Melanie Dani","email":"","orcid":"","institution":"Cutrale Perioperative and Ageing Group, Department of Bioengineering, Imperial College London, London","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Melanie","middleName":"","lastName":"Dani","suffix":""},{"id":102451458,"identity":"4fe10cf4-b3a4-45b2-bd5c-f216b617dd8a","order_by":7,"name":"Michael Fertleman","email":"data:image/png;base64,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","orcid":"","institution":"Cutrale Perioperative and Ageing Group, Department of Bioengineering, Imperial College London, London","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Fertleman","suffix":""}],"badges":[],"createdAt":"2022-04-27 17:44:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1602134/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1602134/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":21029292,"identity":"f2124253-79f9-46c3-ab40-a77e2ec8a176","added_by":"auto","created_at":"2022-05-03 15:54:55","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":98908,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePost-operative changes in CSF cytokines\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eLevels of cytokines in cerebrospinal fluid (CSF) before surgery (T1) and the day after surgery (T2). Each patient is represented by a colour that is consistent across the box-plots. Only cytokines that showed statistically significant changes following surgery are shown.\u0026nbsp;\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-1602134/v1/770bceafdfeb78b1748e3a17.png"},{"id":21029294,"identity":"14d1c4de-4fe0-4d48-871c-faedb74448f4","added_by":"auto","created_at":"2022-05-03 15:54:55","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":265840,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCorrelation plots between CSF cytokines before and after surgery\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eCorrelation plots between cytokines for cerebrospinal fluid (CSF) before surgery (T1) and the day after surgery (T2).\u0026nbsp;\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-1602134/v1/936a4a5d731c3611f4ab6f3c.png"},{"id":21029568,"identity":"33d035b9-bdad-4a18-9075-6857679e8608","added_by":"auto","created_at":"2022-05-03 15:59:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":460842,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1602134/v1/c8bd304a-4370-4104-90f4-55f3748df223.pdf"},{"id":21029567,"identity":"2df2a77c-ec64-4006-8da1-2233b9ec20db","added_by":"auto","created_at":"2022-05-03 15:59:55","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":142068,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaryinformation22.4.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1602134/v1/2101ecf8324d048b76fbffe2.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Cytokine Changes in Cerebrospinal Fluid Following Vascular Surgery on the Thoracic Aorta","fulltext":[{"header":"Background:","content":"\u003cp\u003eNeuroinflammation and its role in delirium and post-operative cognitive dysfunction is complex and incompletely understood. For example, neuroinflammation can lead to Alzheimer\u0026rsquo;s disease (AD) progression [1,\u0026nbsp;2]. On the other hand, a degree of neuroinflammation in AD may be protective, as the cytokines IL-6 and TNF-\u0026alpha; are involved in the clearance of amyloid plaques [3,\u0026nbsp;4].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis raises the question of whether the neuroinflammatory process could also drive peri-operative neurocognitive disorders (PND), such as post-operative delirium (POD). PND is the commonest post-operative complication in older patients undergoing surgery and is associated with worse clinical outcomes [5]; understanding its pathophysiology is essential for developing prevention and cure.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOne hypothesis for the aetiology of PND is that a physiological insult from surgery induces the release of local inflammatory mediators (such as cytokines) from macrophages at the surgical site [6]. An intact blood-brain-barrier (BBB) prevents these inflammatory mediators from affecting the closely regulated environment of the CNS. However if the BBB is weakened by aging, neurodegeneration [7], or the response to a surgical insult [8], inflammatory mediators can enter the CNS. The processes by which the BBB may become weakened are complex, but in AD, this includes brain capillary leakage, cellular infiltration, degeneration of pericytes and loss of endothelial integrity [7]. Once inflammatory mediators enter the CNS, microglial activation occurs, which drives further inflammation, partly through cytokine release [9,\u0026nbsp;10]. Cytokine release and the inflammatory response can then trigger neuronal injury and dysfunction [7], which theoretically could manifest as PND. There is currently no treatment for PND [11]. If the process of neuroinflammation can be better understood, this may open the door to cytokine manipulation, potentially reducing levels of consequent PND. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePrevious investigations on peri-operative cytokine changes has shown greater increases in CSF cytokines than serum or plasma cytokines after an operation [12,\u0026nbsp;13,\u0026nbsp;14]. This suggests a key role for CSF cytokines in post-operative neuroinflammation. However, the number of patients involved in these studies was small. There is a further suggestion that the CSF cytokines, IL-6 and IL-8, are increased in patients with worse neurocognitive outcomes, but again the sample sizes of these studies are inadequately powered to provide definitive evidence [13,\u0026nbsp;15].\u003c/p\u003e\n\u003cp\u003eTo date, only one study has investigated peri-operative changes in both CSF and serum following vascular surgery on the thoracic aorta [16]. In this study of 23 patients, the cytokine IL-6 was increased in both serum and CSF after the operation. In patients with spinal cord injury, the CSF IL-6 increase was more marked. While this study examined a wide variety of proteins relevant to neurology, the number of cytokines studied was small.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSpinal cord injury leading to paraplegia is the most devastating consequence of morbidity following surgery on the thoracic aorta [17]. Draining CSF intraoperatively with a spinal catheter has been shown to reduce the chances of this complication [18], by increasing blood flow to the spinal cord [19]. As such patients already have a spinal catheter in place. This allows for easy access to CSF peri-operatively, making patients undergoing thoracic-vascular surgery a valuable cohort for studying neuroinflammation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe investigated cytokines with both a pro-inflammatory role (IL-1\u0026beta;, IL-6, IL-8, IL-12p70, IFN-\u0026gamma; and TNF-\u0026alpha;) and those with an anti-inflammatory role (IL-2, IL-4, IL-10 and IL-13) [20,\u0026nbsp;21] in a cohort of patients undergoing vascular surgery. The aim of this study was to evaluate the neuroinflammatory response to vascular surgery in order to:\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eDetermine changes in pro- and anti-inflammatory CSF cytokines before and after vascular surgery.\u003c/li\u003e\n \u003cli\u003eInvestigate potential intercorrelations between cytokines in the CSF, to establish whether multiple cytokines are involved in driving neuroinflammation.\u003c/li\u003e\n \u003cli\u003eEstablish if the changes in CSF cytokines are reflected in serum cytokine levels. \u0026nbsp;If so, this would enable serum cytokines to be used as biomarkers of CSF changes.\u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Methods:","content":"\u003cp\u003eThis was a prospective observational study looking at peri-operative changes in cytokine levels in the CSF and serum of patients undergoing elective vascular surgery for any pathology of the thoracic aorta.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients were eligible for recruitment into the study if they were undergoing either open or endovascular repair for any thoracic aortic pathology in which a spinal catheter was to be used as part of standard peri-operative care. The decision about whether a spinal catheter would be used during an operation was a joint decision made pre-operatively in the vascular multidisciplinary team meeting involving the operating surgeon and anaesthetist. Patients did not have neuroimaging performed before or after the operation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRecruitment took place at St Mary\u0026rsquo;s Hospital, London, over a one-year period. Patients unable to give informed written consent were excluded from the study. The study received approval from the London Westminster Research Ethic Committee (13/LO/0210). The study conformed to the precepts set out in the Declaration of Helsinki of 1975.\u0026nbsp;All patients gave informed, written consent prior to surgery.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSpecimen collection and storage\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy patients had a spinal catheter inserted prior to surgery by an anaesthetist, following administration of a general anaesthetic. The spinal catheter was used to maintain the CSF pressure at 10mmHg. If the pressure rose above 10mmHg, CSF was slowly drained until the target was met. CSF was collected by the same operator (author AP) prior to surgery and on the first post-operative day. \u0026nbsp;Approximately 1-3mL of CSF was collected each time. The spinal catheter was removed when it was no longer clinically indicated. Samples were centrifuged at 4000RPM for 5 min to remove any red blood cells present in the sample. Samples were then pipetted into cryo-tubes in 500\u0026mu;L aliquots and stored in a -80\u0026ordm;C freezer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImmunoassays\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe V-PLEX Proinflammatory Panel 1 Human Kit (Meso Scale Discovery, Maryland, USA) was chosen as it measures both pro-inflammatory (IL-1\u0026beta;, IL-6, IL-8, IL-12p70, IFN-\u0026gamma; and TNF-\u0026alpha;) and anti-inflammatory (IL-2, IL-4, IL-10 and IL-13) cytokines [21]. Analysis followed the manufacturer\u0026rsquo;s instructions (www.mesoscale.com). \u0026nbsp;This method of cytokine measurement in peri-operative CSF and blood samples has been used previously [12]. It uses electrochemiluminescence to quantify the levels of ten cytokines in 25 \u0026mu;L of peri-operative CSF or blood samples.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The range for the lowest level of detection (LLD) was between 0.00861 pg/mL for IL-4 and 0.605 pg/mL for IFN-\u0026gamma;. If samples were above the upper limit of detection (ULD) for the assay, they were diluted in Diluent 2 which was supplied with the kit assay and re-analysed, according to the manufacturer\u0026rsquo;s instructions. This was necessary for a small number of IL-8 measurements. For cytokine levels below the LLD or detected, but below the fit curve, the LLD value for the cytokine assay was used, as previously described [22]. All cytokine analysis was completed in the Infectious Diseases Laboratory at Imperial College London, London.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnalyses were carried out using Python, version 3.7 (available from www.python.org). A Wilcoxon Signed-Rank test with Bonferroni correction was used to examine changes in cytokines before and after surgery. Spearman\u0026rsquo;s rank correlation coefficient, again with a Bonferroni correction, assessed cytokine intercorrelation. An adjusted-p value of \u0026lt;0.05 was considered statistically significant. A power calculation to determine the necessary sample size was not undertaken before starting the study, as the number of patients who would be able to consent and complete the study was anticipated to be small.\u003c/p\u003e"},{"header":"Results:","content":"\u003cp\u003eDuring a 1-year period, ten patients were recruited into the study. Table 1 shows the demographic and pre-operative information for the patients. Four of the patients were female, with a mean age of 65 yrs (SD 12 years). Seven patients had undergone previous vascular surgery, often with serious post-operative morbidity. Two patients died in critical care within 30-days of the operation. No patient developed post-operative paraplegia or a clinically apparent stroke.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTimetable of sample collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients had pre-operative (timepoint 1: T1) and post-operative (timepoint 2: T2) CSF samples taken. Five patients also had simultaneous paired serum samples. Patient 5 had their post-operative samples taken on the day of surgery. \u0026nbsp;Supplementary table S1 summarises the aetiology of the thoracic aorta pathology, the type of vascular surgery and the post-operative complications. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCytokine changes following surgery\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 2 and Figure 1 show the cytokine changes in CSF following surgery. The greatest increases occurred in IL-6 and IL-8, which showed a 63-fold and a 31-fold increase respectively. Six cytokines showed statistically significant increases between T1 and T2 (IL-1\u0026beta;, 2, 6, 8, 10 and 13),\u0026nbsp;as shown in Figure 1. Of the cytokines which showed statistically significant increases, three are traditionally classified as pro-inflammatory (IL-1\u0026beta;, 6 and 8) and three (IL-2, 10 and 13) as anti-inflammatory [20].\u003c/p\u003e\n\u003cp\u003eThe levels of most CSF cytokines tended to rise following surgery. However, levels of IFN-\u0026gamma; and IL-12p70 were generally below the LLD in both the pre-and post-operative CSF samples, so no change could be detected. For the cytokines IL-1\u0026beta;, IL-2 and IL-4, pre-operative levels were often below the LLD, but post-operative levels rose into the detection range.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntercorrelation between CSF cytokines\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFigure 2 shows the intercorrelation between CSF cytokines before and after surgery. At T1, the significant correlations observed in the CSF were between IL-1\u0026beta; and IL-2 (r = 0.95, adjusted-\u003cem\u003ep\u003c/em\u003e \u0026lt;0.001). At T2, there were a number of strong positive correlations between 20 pairs of different cytokines, as shown in Supplementary table S2.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSerum cytokine changes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOnly five of the ten patients had serum samples drawn at the same time as the CSF samples. The greatest increase was in IL-6 which showed a 71-fold increase in serum levels after the operation. There was limited intercorrelation between CSF and serum cytokines. At T1, four combinations of CSF and serum cytokines showed significant correlation (r = 1, adjusted-\u003cem\u003ep\u003c/em\u003e \u0026lt;0.05). These included IL-2 and IL-1\u0026beta;, IL-4 and IL-12, IFN-\u0026gamma; and Il-2 and IL-1\u0026beta; and IL-1\u0026beta;. At T2 there were no significant correlations between the CSF and serum cytokine levels (data not shown).\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"Discussion:","content":"\u003cp\u003e\u003cstrong\u003eCSF cytokine findings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe demonstrated increases in both pro- and anti-inflammatory CSF cytokines after vascular surgery on the thoracic aorta. The most marked increases occurred in the pro-inflammatory cytokines, IL-6 and IL-8. The increases in CSF IL-6 confirm previous findings in a similar cohort [16], whereas, to our knowledge, we are the first group to show similar changes in CSF IL-8. Interleukin-8 is a member of the CXC chemokine family, implicated in a wide variety of inflammatory diseases [23]. CSF IL-8 has been shown to be increased in AD, Parkinson\u0026rsquo;s disease [24] and following traumatic brain injury [25]. In patients undergoing other forms of surgery, findings of marked increases in CSF IL-8 have also been demonstrated [12,\u0026nbsp;14].\u003c/p\u003e\n\u003cp\u003eThe increase in CSF cytokines in this study could have resulted from a dysregulated inflammatory response to the peripheral stimulus of surgery driving neuroinflammation within the brain. Alternatively, these findings may have been secondary to silent cerebral infarcts, which\u0026nbsp;have been shown to be increased following thoracic aortic endovascular procedures [26].\u0026nbsp;Ischaemic strokes\u0026nbsp;have been shown to\u0026nbsp;drive an increase in proinflammatory cytokines\u0026nbsp;[27]. It is also possible that the CSF cytokine changes may have occurred due to other post-operative complications such as endoleaks or infection.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntercorrelation findings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLevels of cytokines in the CSF, while not exhibiting an association with each other prior to surgery, strongly correlate on day one after surgery. Figure 2 highlights the complex balance between pro- and anti-inflammatory cytokines which may drive neuroinflammation. The lack of an association between post-operative CSF and serum samples is consistent with other studies in this area [12,\u0026nbsp;14], and suggests that changes in cytokine levels in blood cannot be used reliably as surrogate markers of CSF cytokine changes.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProposed mechanisms\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe results of this study need to be interpreted alongside the current postulated mechanisms of brain dysfunction. These include excessive neuroinflammation [28], the production of reactive oxygen species (ROS) [29], and dysregulated neurotransmission [30].\u003c/p\u003e\n\u003cp\u003eThese mechanisms are all mediated through activation of microglia, which when stimulated can release ROS [29] and cytokines [31]. Microglia are also key drivers of the kynurenine inflammatory pathway, which, in turn, can drive glutamatergic neurotransmission [32]. In the healthy brain, microglia are fundamental in maintaining tissue homeostasis by removing accumulated debris [29]. However, their overactivity may be harmful in disease states [33].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe postulated mechanisms of brain dysfunction are not mutually exclusive, with multiple mechanisms likely to be acting together [30]. Indeed, pro-inflammatory cytokines have been shown to activate the kynurenine pathway, which in turn leads to the generation of ROS through quinolinic acid production [34]. The cytokine changes demonstrated in this study may therefore have implications for several mechanisms of brain dysfunction.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTherapeutic targets\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn contrast to neurodegenerative processes, peri-operative brain dysfunction occurs at a predictable time point, giving a potential opportunity for prevention [35]. Currently, no effective treatment for PND exists [36]. The suggestion that CSF IL-6 and IL-8 hold a key role in the post-operative neuroinflammatory pathway, raises the question of whether direct cytokine inhibition could attenuate these effects. \u0026nbsp;However, as we have demonstrated in this paper, multiple cytokines, both pro- and anti-inflammatory, increase after an operation and thus blocking the action of only one of these cytokines may not necessarily inhibit neuroinflammation. Furthermore, as has been suggested in Alzheimer\u0026rsquo;s disease, a degree of cytokine-driven neuroinflammation may be neuroprotective [3,4].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLimitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSimilar to many studies in this area, this study had a small patient cohort, which may have limited our ability to demonstrate the true magnitude of peri-operative cytokine changes. Future studies should involve larger sample sizes across multiple settings to address this problem. Samples were only taken at two time points, with one patient\u0026rsquo;s CSF sample taken after surgery on day 0 rather than day 1. This patient was not excluded due to an already small cohort. Within the cohort, the surgical approach was not homogenous, with some patients undergoing open surgery and others undergoing endovascular surgery, which could represent a further complicating factor. \u0026nbsp;The small numbers of patients in different surgical groups limits meaningful comparisons. A further confounder was that seven out of ten patients had undergone previous vascular surgery, often with serious post-operative morbidity. Ideally, this study would have corrected for underlying co-morbidity and baseline inflammatory status. In future studies, neuroimaging, to look for radiological evidence of stroke, should be included to investigate how much of the neuroinflammatory burden may be driven by ischaemic strokes. Finally, we cannot exclude the possibility that the inflammatory response was driven by the insertion of the spinal catheter, rather than surgery or anaesthesia, but this is felt to be unlikely due to the magnitude of cytokine changes [14].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study looked solely at cytokine changes, which is only part of the neuroinflammatory process after surgery [35]. Measurement of the Q-albumin to determine the integrity of the BBB would also have been useful [7]. Future studies would ideally also examine the CSF cell count and immunoglobulin subtypes [37], and other markers of neuronal injury [8] to more fully understand pathophysiological processes. This was not possible within the scope of this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA final key limitation of this study was that patients did not undergo peri-operative cognitive testing. Formal cognitive testing for delirium, using screening tools such as the 4AT [38] and neuropsychological testing, would allow for the more direct investigation of correlations between observed CSF cytokine changes and the magnitude of cognitive dysfunction in PND.\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusions:","content":"\u003cp\u003eAfter vascular surgery there is a large increase in cytokines in the CSF, particularly in the pro-inflammatory cytokines IL-6 and IL-8. This may be secondary to peripheral changes in the circulation crossing the BBB and driving neuroinflammation. \u0026nbsp;A strong correlation was found between CSF cytokines on day one after the operation, suggesting that it may be the balance between multiple pro- and anti-inflammatory cytokines which drives neuroinflammation.\u003c/p\u003e\n"},{"header":"Abbreviations:","content":"\u003cp\u003eAD, Alzheimer\u0026rsquo;s disease; BBB, Blood-brain barrier; CNS, Central nervous system; CSF, Cerebrospinal fluid; IFN-\u0026gamma;, Interferon gamma; IL, Interleukin; LLD, Lower limit of detection; POD, Post-operative delirium; PND, Peri-operative neurocognitive disorders; ROS, Reactive oxygen species; T1, Time-point 1 (pre-operation); T2, Time-point 2 (day 1 post-operation); TEVAR, Thoracic endovascular aortic repair; TNF-\u0026alpha;, Tumour necrosis factor alpha; ULD, Upper limit of detection. \u003c/p\u003e"},{"header":"Declarations:","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study received approval from the London Westminster Research Ethic Committee (13/LO/0210). The study conformed to the precepts set out in the Declaration of Helsinki of 1975.\u0026nbsp;All patients gave informed, written consent prior to surgery.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe dataset supporting the conclusions of this article is available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was funded by a grant awarded to Miss\u0026nbsp;Rudarakanchana from the\u0026nbsp;National Institute of Health Research (NIHR) Imperial Biomedical Research Centre (BRC)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors acknowledge the United Kingdom National Institute for Health Research (NIHR) Biomedical Facility at Imperial College London for infrastructure support. SDT-R was funded by a Wellcome Trust ISSF grant at Imperial College London\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eC.P. \u0026ndash; undertook all cytokine experiments and writing of the manuscript. A.H.P. was responsible for patient recruitment and biofluid collection. N.R. offered supervision with the project M.D. \u0026ndash; undertook manuscript review. B.H.L.H. \u0026ndash; undertook statistical analysis. M.D.G. \u0026ndash; undertook statistical analysis. S.D.T.R. \u0026ndash; offered guidance and supervision with the project and manuscript review. M.F. \u0026ndash; was responsible for supervision of the project and manuscript review. All authors reviewed the manuscript.\u003c/p\u003e"},{"header":"References:","content":"\u003col\u003e\n \u003cli\u003e\u003cspan\u003eHeneka, M. T. \u003cem\u003eet al.\u003c/em\u003e Neuroinflammation in Alzheimer\u0026rsquo;s disease. The Lancet Neurology vol.\u0026nbsp;14 388\u0026ndash;405 (2015).\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eDomingues, C., da Cruz e Silva, O. A. B. \u0026amp; Henriques, A. G. Impact of Cytokines and Chemokines on Alzheimer\u0026rsquo;s Disease Neuropathological Hallmarks. \u003cem\u003eCurr. Alzheimer Res.\u003c/em\u003e \u003cstrong\u003e14\u003c/strong\u003e, (2017).\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eChakrabarty, P. \u003cem\u003eet al.\u003c/em\u003e Massive gliosis induced by interleukin-6 suppresses A\u0026beta; deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. FASEB J. \u003cstrong\u003e24\u003c/strong\u003e, 548\u0026ndash;559 (2010).\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eChakrabarty, P., Herring, A., Ceballos-Diaz, C., Das, P. \u0026amp; Golde, T. E. Hippocampal expression of murine TNF results in attenuation of amyloid deposition in vivo. Mol. Neurodegener. \u003cstrong\u003e6\u003c/strong\u003e, (2011).\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eEvered, L., Atkins, K., Silbert, B. \u0026amp; Scott, D. A. Acute peri-operative neurocognitive disorders: a narrative review. Anaesthesia \u003cstrong\u003e77\u003c/strong\u003e, 34\u0026ndash;42 (2022).\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eMarcantonio, E. R. Postoperative delirium: A 76-year-old woman with delirium following surgery. JAMA - J. Am. Med. Assoc. \u003cstrong\u003e308\u003c/strong\u003e, 73\u0026ndash;81 (2012).\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eSweeney, M. D., Sagare, A. P. \u0026amp; Zlokovic, B. V. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. 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The role of neuroinflammation in postoperative cognitive dysfunction: Moving from hypothesis to treatment. Frontiers in Psychiatry vol.\u0026nbsp;9 752 (2019).\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eFertleman, M. \u003cem\u003eet al.\u003c/em\u003e Cytokine changes in cerebrospinal fluid and plasma after emergency orthopaedic surgery. Sci. Rep. \u003cstrong\u003e12\u003c/strong\u003e, 2221 (2022).\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eHirsch, J. \u003cem\u003eet al.\u003c/em\u003e Perioperative cerebrospinal fluid and plasma inflammatory markers after orthopedic surgery. J. Neuroinflammation \u003cstrong\u003e13\u003c/strong\u003e, 211 (2016).\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eBromander, S. \u003cem\u003eet al.\u003c/em\u003e Changes in serum and cerebrospinal fluid cytokines in response to non-neurological surgery: an observational study. J. 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Surg. \u003cstrong\u003e21\u003c/strong\u003e, 13\u0026ndash;20 (2008).\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eMiyamoto, K., Ueno, A., Wada, T. \u0026amp; Kimoto, S. A new and simple method of preventing spinal cord damage following temporary occlusion of the thoracic aorta by draining the cerebrospinal fluid. J. Cardiovasc. Surg. (Torino). \u003cstrong\u003e1\u003c/strong\u003e, 188\u0026ndash;197 (1960).\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eEpstein, N. Cerebrospinal fluid drains reduce risk of spinal cord injury for thoracic/thoracoabdominal aneurysm surgery: A review. Surgical Neurology International vol.\u0026nbsp;9 (2018).\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eDinarello, C. A. Historical insights into cytokines. European Journal of Immunology vol.\u0026nbsp;37 S34\u0026ndash;S45 (2007).\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eMeso Scale Discovery. Proinflammatory Panel 1 (human) Kits. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.mesoscale.com/~/media/files/product inserts/proinflammatory\u003c/span\u003e\u003c/span\u003e panel 1 human insert.pdf (2020).\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eThwaites, R. S. \u003cem\u003eet al.\u003c/em\u003e Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19. Sci. Immunol. \u003cstrong\u003e6\u003c/strong\u003e, (2021).\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eRoebuck, K. A. Regulation of interleukin-8 gene expression. Journal of Interferon and Cytokine Research vol.\u0026nbsp;19 429\u0026ndash;438 (1999).\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eZhang, J. \u003cem\u003eet al.\u003c/em\u003e CSF Multianalyte Profile Distinguishes Alzheimer and Parkinson Diseases. Am. J. Clin. 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M. \u0026amp; Colonna, M. \u003cem\u003eThe identity and function of microglia in neurodegeneration\u003c/em\u003e. \u003cem\u003eNature Immunology\u003c/em\u003e vol.\u0026nbsp;19 1048\u0026ndash;1058 (Nature Publishing Group, 2018).\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eHughes, T. D., G\u0026uuml;ner, O. F., Iradukunda, E. C., Phillips, R. S. \u0026amp; Bowen, J. P. The Kynurenine Pathway and Kynurenine 3-Monooxygenase Inhibitors. \u003cem\u003eMolecules\u003c/em\u003e vol.\u0026nbsp;27 273 (2022).\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eSaxena, S., Kruys, V., Vamecq, J. \u0026amp; Maze, M. The Role of Microglia in Perioperative Neuroinflammation and Neurocognitive Disorders. Frontiers in Aging Neuroscience vol.\u0026nbsp;13 (2021).\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eStone, T. W., Forrest, C. M. \u0026amp; Darlington, L. G. Kynurenine pathway inhibition as a therapeutic strategy for neuroprotection. 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Sci. \u003cstrong\u003e184\u003c/strong\u003e, 101\u0026ndash;122 (2001).\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eBellelli, G. \u003cem\u003eet al.\u003c/em\u003e Validation of the 4AT, a new instrument for rapid delirium screening: A study in 234 hospitalised older people. Age Ageing \u003cstrong\u003e43\u003c/strong\u003e, 496\u0026ndash;502 (2014).\u003c/span\u003e\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1: Demographic and Pre-operative Information\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"6.022187004754358%\"\u003eID\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.705229793977813%\"\u003eSex\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.705229793977813%\"\u003eAge\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"27.099841521394612%\"\u003ePast Medical History\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"27.099841521394612%\"\u003ePast Surgical History\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"28.367670364500793%\"\u003eDrug History\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"6.022187004754358%\"\u003e4\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.705229793977813%\"\u003eF\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.705229793977813%\"\u003e73\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"27.099841521394612%\"\u003eHTN, high cholesterol, ex-smoker\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"27.099841521394612%\"\u003eCarotid-subclavian bypass\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"28.367670364500793%\"\u003eBisoprolol, paracetamol, simvastatin\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"6.022187004754358%\"\u003e5\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.705229793977813%\"\u003eM\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.705229793977813%\"\u003e80\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"27.099841521394612%\"\u003eCABG, high cholesterol, prostate cancer\u0026nbsp;\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"27.099841521394612%\"\u003eRadical prostatectomy, EVAR\u0026nbsp;\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"28.367670364500793%\"\u003eAspirin, simvastatin, omeprazole, paracetamol\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"6.022187004754358%\"\u003e10\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.705229793977813%\"\u003eF\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.705229793977813%\"\u003e56\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"27.099841521394612%\"\u003eEndometriosis, HTN, high cholesterol, ex-smoker\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"27.099841521394612%\"\u003eHybrid-vascular surgery (2008)\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"28.367670364500793%\"\u003eAtorvastatin, amlodipine, perindopril\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"6.022187004754358%\"\u003e12\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.705229793977813%\"\u003eF\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.705229793977813%\"\u003e77\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"27.099841521394612%\"\u003eLeft occipital ischaemic stroke, asthma, IHD, T2DM, high cholesterol, HTN\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"27.099841521394612%\"\u003eNil\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"28.367670364500793%\"\u003eNR\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"6.022187004754358%\"\u003e13\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.705229793977813%\"\u003eF\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.705229793977813%\"\u003e40\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"27.099841521394612%\"\u003eHTN, Marfan syndrome with pectus excavatum and dural ectasia, heart failure\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"27.099841521394612%\"\u003eType A aortic dissection - emergency aortic valve sparing open replacement of root/ascending aorta and proximal arch (2007), arch hybrid (2012)- post operative cardiac arrest followed by tracheostomy, myopathy and prolonged ITU stay.\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"28.367670364500793%\"\u003eAmlodipine, perindopril, bisoprolol, aspirin, spironolactone\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"6.022187004754358%\"\u003e18\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.705229793977813%\"\u003eM\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.705229793977813%\"\u003e54\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"27.099841521394612%\"\u003eMarfan syndrome, ICD, blind, bilateral cataracts, stroke, HTN, high cholesterol, T2DM\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"27.099841521394612%\"\u003eOpen arch and DTA replacement, AVR, and ascending aorta to LCCA bypass, post operative occipital infarct, haemorrhage and large SDH requiring craniotomy and evacuation.\u0026nbsp;\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"28.367670364500793%\"\u003eAmlodipine, indapamide, metoprolol, senna, doxazosin, gliclazide, losartan, pregabalin, lansoprazole, paracetamol, warfarin, tinzaparin,\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"6.022187004754358%\"\u003e20\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.705229793977813%\"\u003eM\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.705229793977813%\"\u003e74\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"27.099841521394612%\"\u003eParaplegia, CKD\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"27.099841521394612%\"\u003eOpen type 2 thoracic aorta repair (2000), then dilatation of visceral aortic patch\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"28.367670364500793%\"\u003eNR\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"6.022187004754358%\"\u003e24\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.705229793977813%\"\u003eM\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.705229793977813%\"\u003e62\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"27.099841521394612%\"\u003eHTN\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"27.099841521394612%\"\u003eNil\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"28.367670364500793%\"\u003eCarvedilol\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"6.022187004754358%\"\u003e25\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.705229793977813%\"\u003eM\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.705229793977813%\"\u003e72\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"27.099841521394612%\"\u003eHTN, high cholesterol, current smoker, T2DM, COPD\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"27.099841521394612%\"\u003eNil\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"28.367670364500793%\"\u003eNR\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"6.022187004754358%\"\u003e27\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.705229793977813%\"\u003eM\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"5.705229793977813%\"\u003e65\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"27.099841521394612%\"\u003eHTN, high cholesterol, smoker, COPD, schizophrenia\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"27.099841521394612%\"\u003eEVAR (2013)\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"28.367670364500793%\"\u003eAmlodipine, procyclidine\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eKey: AVR = Aortic valve replacement, CKD = Chronic kidney disease, CABG = Coronary artery bypass graft, COPD = Chronic obstructive pulmonary disease, DTA = Descending thoracic aorta, EVAR = Endovascular aneurysm repair, HTN = Hypertension, ICD = Implantable Cardioverter Defibrillator, IHD = Ischaemic heart disease, ITU = Intensive therapy unit, LCCA = left common carotid artery, NR = Not recorded, SHD = Subdural haematoma, T2DM = Type 2 Diabetes\u003c/p\u003e\n\u003cp\u003eLegend: A table showing the medical and surgical backgrounds for the ten patients included in this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2: Summary of cytokine measurements in CSF\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15.946843853820598%\"\u003eCytokine\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.956810631229235%\"\u003eTimepoint\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"32.89036544850498%\"\u003eCSF Median [IQR]\u0026nbsp;\u003cbr\u003e(pg/mL)\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.421926910299003%\"\u003eAdjusted-\u003cem\u003ep\u003c/em\u003e value Wilcoxon Signed-Rank Test between T1 and T2\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.784053156146179%\"\u003eAverage fold change\u0026nbsp;\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15.946843853820598%\"\u003eIL-1\u0026beta;\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.956810631229235%\"\u003eT1\u003cbr\u003eT2\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"32.89036544850498%\"\u003e0.14 [0.14 \u0026ndash; 0.15]\u003cbr\u003e0.60 [0.36 \u0026ndash; 0.84]\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.421926910299003%\"\u003e\u0026lt;0.01\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.784053156146179%\"\u003e5.4\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15.946843853820598%\"\u003eIL-2\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.956810631229235%\"\u003eT1\u003cbr\u003eT2\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"32.89036544850498%\"\u003e0.20 [0.20 \u0026ndash; 0.23]\u003cbr\u003e0.30 [0.21 \u0026ndash; 0.81]\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.421926910299003%\"\u003e\u0026lt;0.05\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.784053156146179%\"\u003e4.6\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15.946843853820598%\"\u003eIL-4\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.956810631229235%\"\u003eT1\u003cbr\u003eT2\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"32.89036544850498%\"\u003e0.02 [0.01 \u0026ndash; 0.03]\u003cbr\u003e0.03 [0.01 \u0026ndash; 0.08]\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.421926910299003%\"\u003ens\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.784053156146179%\"\u003e4.5\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15.946843853820598%\"\u003eIL-6\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.956810631229235%\"\u003eT1\u003cbr\u003eT2\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"32.89036544850498%\"\u003e0.98 [0.39 \u0026ndash; 1.28]\u003cbr\u003e15.91 [9.73 \u0026ndash; 62.57]\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.421926910299003%\"\u003e\u0026lt;0.01\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.784053156146179%\"\u003e63.3\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15.946843853820598%\"\u003eIL-8\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.956810631229235%\"\u003eT1\u003cbr\u003eT2\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"32.89036544850498%\"\u003e26.85 [9.35 \u0026ndash; 42.32]\u003cbr\u003e919.23 [333.42 \u0026ndash; 1366.63]\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.421926910299003%\"\u003e\u0026lt;0.01\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.784053156146179%\"\u003e31.0\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15.946843853820598%\"\u003eIL-10\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.956810631229235%\"\u003eT1\u003cbr\u003eT2\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"32.89036544850498%\"\u003e0.30 [0.19 \u0026ndash; 0.43]\u003cbr\u003e0.85 [0.37 \u0026ndash; 1.00]\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.421926910299003%\"\u003e\u0026lt;0.05\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.784053156146179%\"\u003e4.5\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15.946843853820598%\"\u003eIL-12p70\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.956810631229235%\"\u003eT1\u003cbr\u003eT2\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"32.89036544850498%\"\u003e0.09 [0.08 \u0026ndash; 0.17]\u003cbr\u003e0.11 [0.08 \u0026ndash; 0.12]\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.421926910299003%\"\u003ens\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.784053156146179%\"\u003e2.8\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15.946843853820598%\"\u003eIL-13\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.956810631229235%\"\u003eT1\u003cbr\u003eT2\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"32.89036544850498%\"\u003e1.14 [0.55 \u0026ndash; 1.86]\u003cbr\u003e2.78 [1.67 \u0026ndash; 12.75]\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.421926910299003%\"\u003e\u0026lt;0.01\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.784053156146179%\"\u003e5.2\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15.946843853820598%\"\u003eIFN-\u0026gamma;\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.956810631229235%\"\u003eT1\u003cbr\u003eT2\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"32.89036544850498%\"\u003e0.605 [0.54 \u0026ndash; 0.67]\u003cbr\u003e0.605 [0.54 \u0026ndash; 0.63]\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.421926910299003%\"\u003ens\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.784053156146179%\"\u003e2.6\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"15.946843853820598%\"\u003eTNF-\u0026alpha;\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"12.956810631229235%\"\u003eT1\u003cbr\u003eT2\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"32.89036544850498%\"\u003e0.52 [0.32 \u0026ndash; 0.96]\u003cbr\u003e0.99 [0.51 \u0026ndash; 2.10]\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.421926910299003%\"\u003ens\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" width=\"14.784053156146179%\"\u003e3.9\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eLegend: Cytokine levels in cerebrospinal fluid (CSF) before surgery (T1) and the day after surgery (T2), ns = non-significant\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Neuroinflammation, cerebrospinal fluid, vascular surgery, cytokines, interleukins, central nervous system","lastPublishedDoi":"10.21203/rs.3.rs-1602134/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1602134/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\u003cp\u003eThere is growing evidence that surgery can drive an inflammatory response in the brain. However, the mechanisms behind this response are incompletely understood. Neuroinflammation may contribute to peri-operative neurocognitive disorders (PND), including post-operative delirium (POD). Here, we investigate the hypotheses that 1. Cerebrospinal fluid (CSF) cytokines increase after vascular surgery and 2. That these changes in CSF cytokines are interrelated.\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\u003cp\u003ePatients undergoing either open or endovascular elective surgery of the thoracic aorta were invited to participate in this study. Cerebrospinal fluid samples were taken before surgery and on the first post-operative day. These were analysed for the presence of ten cytokines by immunoassay to examine for post-operative changes in cytokine levels. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\u003cp\u003eAfter surgery, there were significant increases in six out of the ten measured CSF cytokines (IL-1β, 2, 6, 8, 10 and 13). This included changes in both putative pro-inflammatory (IL-1β, 6 and 8) and putative anti-inflammatory (IL-2, 10 and 13) cytokines. The greatest increases occurred in IL-6 and IL-8, which showed a 63-fold and a 31-fold increase respectively. There was strong intercorrelation between CSF cytokines after the operation. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eFollowing surgery on the thoracic aorta, there was a marked increase in CSF cytokines, consistent with a potential role in neuroinflammation. The ten measured cytokines showed intercorrelation after the operation, indicating that a balance between multiple pro- and anti-inflammatory cytokines may be present. This could be detrimental, protective, or both.\u0026nbsp;\u003c/p\u003e","manuscriptTitle":"Cytokine Changes in Cerebrospinal Fluid Following Vascular Surgery on the Thoracic Aorta","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-05-03 15:54:53","doi":"10.21203/rs.3.rs-1602134/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2022-06-28T09:14:28+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2022-06-25T14:08:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"3ac0057a-8d06-4a37-be8d-f3b27d3e43fa","date":"2022-06-13T15:29:45+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2022-05-11T05:43:20+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2022-05-11T05:21:42+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2022-04-29T13:46:55+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2022-04-29T13:46:10+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2022-04-27T17:38:30+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"579bf18a-3f4b-42f4-afb1-2e9c1cb50efa","owner":[],"postedDate":"May 3rd, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2022-07-18T07:29:21+00:00","versionOfRecord":[],"versionCreatedAt":"2022-05-03 15:54:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1602134","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1602134","identity":"rs-1602134","version":["v1"]},"buildId":"-D5TCW68w8eVRRLyjaTIo","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}